Desmethylolanzapine compositions and methods

ABSTRACT

Methods and compositions are disclosed utilizing N-desmethylolanzapine for the treatment of psychosis in humans. N-Desmethylolanzapine exhibits a lessened liability toward drug-drug interactions than olanzapine and a more predictable dosing regimen than olanzapine. N-Desmethylolanzapine is also useful for the treatment of acute mania, mild anxiety states, anxiety disorders, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autistic disorder, excessive aggression, substance abuse, depressive signs and symptoms, tic disorder, functional bowel disorder and fungal dermatitis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. non-provisional application, Ser.No. 09/444,590, filed on Nov. 22, 1999 now U.S. Pat. No. 6,348,455,which claims priority from U.S. provisional application, Ser. No.60/109,584, filed on Nov. 23, 1998.

FIELD OF THE INVENTION

The invention relates to methods of treating psychosis, acute mania,mild anxiety states, schizophrenia, bipolar disorder, autistic disorder,excessive aggression, substance abuse, depressive signs and symptoms,tic disorder, functional bowel disorder and fungal dermatitis.

BACKGROUND OF THE INVENTION

Olanzapine I is an orally active, potent, antipsychotic agent.

It is commercially available as Zyprexa® from Eli Lilly Co. Theantipsychotic effect of olanzapine is ascribed by the literature toblocking of the dopamine D₂ receptor and to 5-HT antagonism.

One of the main serum metabolites of olanzapine is N-desmethylolanzapineII, formed by oxidation demethylation of the nitrogen at the 4-positionof the piperazinyl ring. The chemical name of II is2-methyl-4-(1-piperazinyl)-10H-thieno[2.3-b][1,5]benzodiazepine andhereinafter is referred to as desmethylolanzapine.

Formation of desmethylolanzapine occurs in the liver through the enzymesof the P450 system, specifically CYP1A2. Other drugs which inhibit theCYP1A2 isoenzyme may interfere with the formation of this metabolite. Inaddition, coadministration of drugs also metabolized by CYP1A2 may leadto elevated blood concentrations of one or both drugs throughcompetitive inhibition. Specifically, known inhibitors of CYP1A2 such asfluvoxamine and quinoline antibiotics (ciprofloxacin) may interfere withthe demethylation of olanzapine. Compounds which are inducers of CYP1A2may cause faster metabolism of olanzapine in exposed persons. Inaddition, men appear to exhibit higher CYP1A2 activity than women,resulting in gender-related differences in olanzapine metabolism.

It is therefore desirable to find a compound with the advantages ofolanzapine which would provide a more predictable dosage regimen in thepatient population and that would decrease the chances for drugdruginteraction.

SUMMARY OF THE INVENTION

The present invention relates to use of desmethylolanzapine for treatingpsychosis, acute mania, mild anxiety states, anxiety disorders,schizophrenia, bipolar disorder, autistic disorder, attention deficithyperactivity disorder (“ADHD”), excessive aggression, substance abuse,depressive signs and symptoms, tic disorder, functional bowel disorderand fungal dermatitis. It provides this effective treatment whileexhibiting fewer or less severe adverse effects than olanzapine, alessened liability toward drug-drug interactions than olanzapine and amore predictable dosing regimen than olanzapine.

The invention also relates to pharmaceutical compositions comprisingdesmethylolanzapine. In one embodiment, said pharmaceutical compositionscomprise solid unit dosage forms such as tablets or capsules, containingdesmethylolanzapine.

DETAILED DESCRIPTION OF THE INVENTION

The active compound of the compositions and methods of the presentinvention is desmethylolanzapine. It may be prepared as described byCalligaro et al., [Biorg. & Med. Chem. Letters, 1, 25-30, (1997)], thedisclosure of which is incorporated herein by reference. Calligaroconcludes that the “data demonstrate that all metabolites aresignificantly less active than olanzapine. It is therefore unlikely thatthe activity of these agents contributes to the overall pharmacologicalprofile of the parent compound.” Galatsis [Annual Reports in MedicinalChemistry 32, 313, (1997)] also states that olanzapine's “ten metabolicproducts are inactive.” Kando et al. [The Annals of Pharmacotherapy, 31,1325-1334, (1997)] report that the metabolites “lack antipsychoticactivity at the concentrations that have been observed.”

It has now been discovered that desmethylolanzapine is a superior agentfor treating psychoses such as acute mania and schizophrenia, mildanxiety states, anxiety disorders, bipolar disorder, autistic disorder,excessive aggression, attention deficit hyperactivity disorder,substance abuse, depressive signs and symptoms, tic disorder, functionalbowel disorder and fungal dermatitis. In particular, the methods andcompositions of the present invention may be used to treat humanssuffering from such conditions. Desmethylolanzapine provides thiseffective treatment while exhibiting fewer or less severe adverseeffects than olanzapine, a lessened liability toward drug-druginteractions than olanzapine and a more predictable dosing regimen thanolanzapine.

Adverse effects of olanzapine include postural hypotension,constipation, dry mouth, weight gain, dizziness, fast heartbeat,personality disorder and akathisia. Other side effects of olanzapineinclude tachycardia, irregular pulse, diaphoresis, cardiac dysrhythmia,flu syndrome, nausea, vomiting, hematuria, metrorrhagia, urinaryincontinence, abdominal pain, premenstrual syndrome, somnolence,agitation, insomnia, nervousness, headache, dyspnea, tremors,myoglobinuria (rhabdomyolysis), drug-induced Parkinsonism, amblyopia,and asthenia.

The present invention encompasses a method of treating psychosis whichcomprises administering to a human in need of such therapy, an amount ofdesmethylolanzapine or a pharmaceutically acceptable salt thereof, saidamount being sufficient to alleviate the symptoms of the psychoticcondition. Psychotic conditions of particular interest in humansinclude, but are not limited to, ADHD, schizophrenia and acute mania.

The present invention also encompasses an oral composition whichcomprises a pharmaceutically acceptable carrier for oral administrationand a therapeutically effective amount of desmethylolanzapine or apharmaceutically acceptable salt thereof. Preferably the composition isin the form of a tablet or capsule, and the amount ofdesmethylolanzapine in the tablet or capsule is preferably about 1 to150 mg.

A pharmaceutical composition of the present invention may also contain atherapeutically effective amount of a selective serotonin reuptakeinhibitor in addition to a therapeutically effective amount ofdesmethylolanzapine or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier for oral administration. Selectiveserotonin reuptake inhibitors include, but are not limited to paroxetine(PAXIL®), fluoxetine (PROZAC®), sertaline (ZOLOFT®), fluvoxamine(LUVOX®), venlafaxine (EFFEXOR®), and nefazodone (SERZONE®), as well asany optically pure isomers or metabolites of any of these compounds.

The present invention further encompasses a method of treating bipolardisorder, anxiety disorder, tic disorder, autistic disorder, excessiveaggression, substance abuse, and signs and symptoms of depression and oftreating conditions caused or contributed to by any of these. The methodcomprises administering to a human in need of such therapy, an amount ofdesmethylolanzapine or a pharmaceutically acceptable salt thereof, saidamount being sufficient to alleviate the symptoms of the particularcondition.

The present invention further encompasses a method of treating fungaldermatitis and functional bowel disorder. The method comprisesadministering to a human in need of such therapy, an amount ofdesmethylolanzapine or a pharmaceutically acceptable salt thereof, saidamount being sufficient to alleviate the symptoms of the particularcondition.

Utilizing desmethylolanzapine results in enhanced dosage predictabilityand an improved therapeutic index. In particular, desmethylolanzapineexhibits less potential for drug-drug interaction than does olanzapine,where CYP1A2 inhibitors or inducers are coadministered.Desmethylolanzapine may also be used to treat various conditions ordisorders while minimizing or avoiding adverse cardiac events associatedwith administration of olanzapine. Furthermore, desmethylolanzapine canbe administered to treat various conditions or disorders whileminimizing or avoiding impact on hepatic function (e.g., liver enzymeabnormalities).

The term “psychotic condition” as used herein means pathologicpsychological conditions which are psychoses or may be associated withpsychotic features. Such conditions include, but are not limited to thepsychotic disorders which have been characterized in the DSM-IV-R,Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed.(1994), including schizophrenia and acute mania. The DSM-IV-R wasprepared by the Task Force on Nomenclature and Statistics of theAmerican Association, and provides clear descriptions of diagnosticcategories. The skilled artisan will recognize that there arealternative nomenclatures, nosologies, and classification systems forpathologic psychological conditions and that these systems evolve withmedical scientific progress.

The term “bipolar disorder” as used herein refers to a conditioncharacterized as a Bipolar disorder, in the DSM-IV-R as category 296.xx,including both Bipolar Disorder I and Bipolar Disorder II.

The term “autistic disorder” as used herein means a conditioncharacterized as an Autistic Disorder in the DSM-IV-R as category299.xx, including 299.00, 299.80, and 299.10, preferably 299.00.

The term “anxiety disorders” includes, but is not limited to,obsessive-compulsive disorder, psychoactive substance anxiety disorder,post-traumatic stress disorder, generalized anxiety disorder, anxietydisorder NOS, and organic anxiety disorder.

The term “substance abuse” as used herein means the undesired physicaland/or psychological dependence on a drug. The term refers to dependenceon a substance such as cocaine, psychedelic agents, marijuana,amphetamines, hallucinogen, phencyclidine, benzodiazepines, alcohol andnicotine.

The terms “attention deficit hyperactivity disorder” and ADHD” as usedherein mean a condition or disorder characterized by a persistentpattern of inattention, hyperactivity, impulsivity, or any combinationthereof.

The term “excessive aggression ” as used herein refers to a conditioncharacterized by aggression that is so excessive that it interferes withthe individual's daily functions, relationships, and may threaten thesafety of the individual, for example in a situation in which violentsuicide is contemplated. The excessive aggression which may be treatedusing the method claimed herein is independent of a psychotic conditionand not directly related to the consumption of a drug or othersubstance.

A tic is a sudden, rapid recurrent, nonrhythmic, stereotyped motormovement or vocalization, experienced as irresistible but suppressiblefor varying lengths of time. Common simple motor tics include eyeblinking, neck jerking, shoulder shrugging, facial grimacing, andcoughing. Common simple vocal tics include throat clearing, grunting,sniffing, snorting, and barking. Common complex motor tics includefacial gestures, grooming behaviors, jumping, touching, stamping, andsmelling an object. Common complex vocal tics include repeating words orphrases out of context, coprolalia (use of socially unacceptable words,frequently obscene) palilalia (repeating one's own sounds or words), andecholalia(repeating the last heard sound, word or phrase). The term “ticdisorder” as used herein means includes tic disorders featuring one ormore motor tics and one or more tic and more vocal tics, and vocal tics.Examples include Transient Tic Disorder. Tourette's Disorder, ChronicVocal Tic Disorder, and Tic Disorder not otherwise specified asdescribed by DSM-IV-R.

The term “functional bowel disorder” refers to a functionalgastrointestinal disorder manifested by (1) abdominal pain, or (2)symptoms of disturbed defecation (urgency, straining, feeling ofincomplete evacuation, altered stool form [consistency] and alteredbowel frequency/timing) or (3) bloating (distension), or any combinationthereof. The term “functional bowel disorder” includes but is notlimited to irritable bowel syndrome, hypermotility, ichlasia, hypertoniclower esophageal sphincter, tachygastria, constipation, andhypermotility associated with irritable bowel syndrome.

The term “treating” as used herein includes prophylaxis of the namedcondition or amelioration or elimination of the condition once it hasbeen established.

The magnitude of a prophylactic or therapeutic dose ofdesmethylolanzapine in the acute or chronic management of disease willvary with the severity of the condition to be treated and the route ofadministration. The dose and perhaps the dose frequency will also varyaccording to the age, body weight and response of the individualpatient. In general, the total daily dose range for desmethylolanzapinefor the conditions described herein is from about 1 to 150 mg in singleor divided doses. In managing the patient, the therapy should beinitiated at a lower dose, perhaps at about 1 mg and increased to adesired dose depending on the patient's global response. It is furtherrecommended that children and patients over 65 years and those withimpaired renal or hepatic function, initially receive low doses, andthat they be titrated based on individual response(s) and bloodlevel(s). It may be necessary to use dosages outside these ranges insome cases as will be apparent to those skilled in the art. Further, itis noted that the clinician or treating physician will know how and whento interrupt, adjust, or terminate therapy in conjunction withindividual patient response.

The relative activity, potency and specificity of desmethylolanzapinecan be determined by a pharmacological study in animals according to themethod of Nyberg et al. [Psychopharmacology 119, 345-348 (1995)]. Thetest provides an estimate of relative activity, potency and, through ameasure of specificity, an estimate of therapeutic index. Other animalstudies which may be used include, but are not limited to, studiesinvolving conditioned avoidance, apomorphine induced climbing, andblockade of 5-hydroxy-tryptophan-induced head twitching. Although thedifferential metabolism among patient populations can be determined by aclinical study in humans, less expensive and time-consuming substitutesare provided by the methods of Kerr et al. [Biochem. Pharmacol. 47,1969-1979 (1994)] and Karam et al. [Drug Metab. Dispos. 24, 1081-1087(1996)]. Similarly, the potential for drug-drug interactions may beassessed clinically according to the methods of Leach et al. [Epilepsia37, 1100-1106 (1996)] or in vitro according to the methods of Kerr etal.[op. cit.] and Turner and Renton [Can. J. Physiol. Pharmacol. 67,582-586 (1989)]. In addition, the relative activity, potency andspecificity of desmethylolanzapine may be tested using various in vitroreceptor assays, including but not limited to assays involving dopaminereceptors, serotonin receptors, adrenergic receptors, and muscarinicreceptors.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of desmethylolanzapine. Rectal, oral,parenteral (subcutaneous, intramuscular, intravenous), transdermal, andlike forms of administration are possible, but oral administration ispreferred. Oral dosage forms include tablets, troches, dispersions,suspensions, solutions, capsules, soft elastic gelatin capsules, and thelike.

The pharmaceutical compositions of the present invention comprisedesmethylolanzapine as the active ingredient, or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier, and optionally, other therapeutic ingredients. In apreferred embodiment, pharmaceutical compositions of the presentinvention comprise desmethylolanzapine in combination with a selectiveserotonin reuptake inhibitor.

The terms “pharmaceutically acceptable salts” or “a pharmaceuticallyacceptable salt thereof” refer to salts prepared from pharmaceuticallyacceptable non-toxic acids. Since the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids including inorganic and organic acids. Suitablepharmaceutically acceptable acid addition salts for the compound of thepresent invention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic (mesylate), mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and thelike.

The compositions of the present invention include suspensions,solutions, elixirs or solid dosage forms. Carriers such as starches,sugars, and microcrystalline cellulose, diluents, granulating agents,lubricants, binders, disintegrating agents, and the like are suitable inthe case of oral solid preparations (such as powders, capsules, andtablets), and oral solid preparations are preferred over the oral liquidpreparations. Oral dosage forms suitable for desmethylolanzapine aredescribed in U.S. Pat. Nos. 5, 229,382 and 5, 605,897 and in PCTapplication WO97/11700, the disclosures of which are incorporated hereinby reference.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered by controlled releaseformulations, which are well known in the art. Compositions suitable forrectal administration are described in European Application 645140, thedisclosure of which is incorporated herein by reference.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, or tablets, each containing a predetermined amount of theactive ingredient, as a powder or granules, or as a solution or asuspension in an aqueous liquid, a non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such compositions may beprepared by any of the methods of pharmacy, but all methods include thestep of bringing into association the active ingredient with the carrierwhich constitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active agent ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet or capsule contains about 1 mg toabout 150 mg of the active ingredient.

An enteric coating, such as the polyacrylate Eudragit L® and Eudragit S®series, is applied, preferably with an aqueous dispersion of the coatingpolymer. Tablets of other strengths may be prepared by altering theratio of active ingredient to the excipients or to the final weight ofthe tablet.

In another embodiment, pharmaceutical compositions of the presentinvention suitable for oral administration may be formulated in a softelastic gelatin capsule unit dosage form using conventional methods(see, e.g., Ebert, Pharm. Tech., 1(5):44-50(1977). Soft elastic gelatincapsules have a soft, globular, gelatin shell somewhat thicker than thatof hard gelatin capsules, wherein a gelatin is plasticized by theaddition of glycerin, sorbitol, or a similar polyol. The hardness of thecapsule shell may be changed by varying the type of gelatin and theamounts of plasticizer and water. The soft gelatin shells may contain apreservative to prevent the growth of fungi, such as methyl -andpropylparabens and sorbic acid. The active ingredient may be dissolvedor suspended in a suitable liquid vehicle or carrier, such as vegetableor mineral oils, glycols such as polyethylene glycol and propyleneglycol, triglycerides, surfactants such as polysorbates, or acombination thereof.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the compositions of the presentinvention, as well as their utility. It will be apparent to thoseskilled in the art that many modifications, both to materials andmethods, may be practiced without departing from the invention.

EXAMPLES

Example 1 - 20 mg Tablets Composition per tablet: desmethylolanzapine 20mg croscarmellose 60 mg colloidal silicon dioxide  8 mg magnesiumstearate  1 mg microcrystalline cellulose 190 mg  croscarmellose 15 mgtalc 10 mg Total 304 mg 

EXAMPLE 1

Desmethylolanzapine and silicon dioxide are dry mixed, the first portionof croscarmellose is added and the mixture is further dry mixed. Themagnesium stearate is added, dry mixed and the mixture is run through aroller compactor and mill. The resulting dry granulate is mixed with theremaining three ingredients and compressed into tablets.

Example 2 - 10 mg Tablets Composition per unit dosage:desmethylolanzapine 10 mg pregelatinized starch 200 mg microcrystallinecellulose 25 mg povidone 15 mg croscarmellose 10 mg magnesium stearate3.75 mg FD & C yellow #2 lake 2.5 mg Water (5 mL) Total 266.25 mg

EXAMPLE 2

The ingredients above are mixed well in the proportions shown in a highshear mixer until uniform granules result. The mixture is tray-dried at40° C. under vacuum until the desired consistency is reached. Thegranules are milled to less than 60 mesh using a screen mill andcompressed into tablets.

What is claimed is:
 1. A method of treating a condition selected fromthe group consisting of mild anxiety state, bipolar disorder, autisticdisorder, attention deficit hyperactivity disorder, excessiveaggression, substance abuse, depression, anxiety disorder, tic disorder,and functional bowel disorder, said method comprising administering to ahuman a therapeutically effective amount of desmethylolanzapine or apharmaceutically acceptable salt thereof.
 2. A method according to claim1, wherein said condition is bipolar disorder.
 3. A method according toclaim 1, wherein said condition is autistic disorder.
 4. A methodaccording to claim 1, wherein said condition is attention deficithyperactivity disorder.
 5. A method according to claim 1, wherein saidcondition is excessive aggression.
 6. A method according to claim 1,wherein said condition is substance abuse.
 7. A method according toclaim 1, wherein said condition is depression.
 8. A method according toclaim 1, wherein said condition is tic disorder.
 9. A method accordingto claim 1, wherein said condition is functional bowel disorder.
 10. Amethod according to claim 1, wherein said condition is anxiety disorder.11. The method according to claim 10, wherein the anxiety disorder isselected from the group consisting of obsessive-compulsive disorder,post-traumatic stress disorder, psychoactive substance disorder,generalized anxiety disorder, organic anxiety disorder, and anxietydisorder NOS.
 12. A pharmaceutical composition comprisingdesmethylolanzapine, or a pharmaceutically acceptable salt thereof, oneor more pharmaceutically acceptable carriers, and a therapeuticallyeffective amount of a selective serotonin reuptake inhibitor compound ora pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition according to claim 12, additionally comprising atherapeutically effective amount of a drug chosen from paroxetine,fluoxetine, sertaline, fluvoxamine, venlafaxine and nefazodone.